International Journal of

Environmental Research

and Public Health

Review

Environmental Chemical Assessment in ClinicalPractice: Unveiling the Elephant in the Room

Nicole Bijlsma † and Marc M. Cohen *,†

School of Health Sciences, RMIT University, Bundoora, Victoria 3083, Australia; s9711185@student.rmit.edu.au* Correspondence: marc.cohen@rmit.edu.au; Tel.: +61-3-9925-7440† These authors contributed equally to this work.

Academic Editor: Paul B. TchounwouReceived: 11 December 2015; Accepted: 27 January 2016; Published: 2 February 2016

Abstract: A growing body of evidence suggests chemicals present in air, water, soil, food, buildingmaterials and household products are toxicants that contribute to the many chronic diseases typicallyseen in routine medical practice. Yet, despite calls from numerous organisations to provide clinicianswith more training and awareness in environmental health, there are multiple barriers to theclinical assessment of toxic environmental exposures. Recent developments in the fields of systemsbiology, innovative breakthroughs in biomedical research encompassing the “-omics” fields, andadvances in mobile sensing, peer-to-peer networks and big data, provide tools that future clinicianscan use to assess environmental chemical exposures in their patients. There is also a need forconcerted action at all levels, including actions by individual patients, clinicians, medical educators,regulators, government and non-government organisations, corporations and the wider civil society,to understand the “exposome” and minimise the extent of toxic exposures on current and futuregenerations. Clinical environmental chemical risk assessment may provide a bridge between multipledisciplines that uses new technologies to herald in a new era in personalised medicine that unitesclinicians, patients and civil society in the quest to understand and master the links between theenvironment and human health.

Keywords: environmental chemical assessment; exposome; clinical practice; toxicant; environmentalmedicine; personalized medicine; systems biology

1. Introduction

Human exposure to environmental chemicals has increased exponentially over the past decadesand a growing body of evidence suggests that chemicals present in air, water, soil, food, buildingmaterials and household products are toxicants that contribute to many of the chronic diseases typicallyseen in clinical practice. Yet, despite the call from numerous organisations for regulatory reform andan increase in training on environmental health for clinicians, environmental chemical assessment isgenerally overlooked in clinical practice and environmental chemicals can be considered as an elephantin the room that is largely ignored.

The failure of genome-wide association studies to explain the vast majority of chronic diseasesnow afflicting 50% of people of working age [1], together with emerging research exploring aberrationsin the epigenome and “exposome” (the total exposures seen during the organism’s life) in the aetiologyof chronic disease [2], has led to a paradigm shift in our understanding of chronic “non-communicable”disease [3]. Furthermore, the “epidemiological transition” from infectious diseases in developingcountries to chronic diseases in developed countries, has led to a fundamental reconsideration of thehealth impact of environmental exposures [4].

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Innovative breakthroughs in biomedical research and technology encompassing the emerging“-omics” fields (epigenomics, nutrigenomics, metabolomics, toxicogenomics), and advances in thefield of classical toxicology, have further contributed to a new understanding of the relationshipbetween chronic diseases and exposures to environmental chemicals across the lifespan. Thisnew understanding validates what Hippocrates stated centuries ago; that one’s diet, lifestyle andenvironment, has profound consequences on health and wellbeing [5], and has wide reachingramifications for the practice of medicine that provides clinicians with unique and important roles toplay in identifying and preventing environmental chemical exposures.

2. The Rise of Chemical Production and Exposures

The number of chemicals in the world is essentially unknown, yet the world’s largest databaseon chemical information—the Chemical Abstracts Service (CAS) RegistrySM established in 1907,currently contains more than 100 million chemicals [6] with around 200,000 new chemicals beingadded each week [7]. While many of these chemicals are produced by natural processes, or areinadvertently produced as by-products of fossil fuel combustion or other industrial processes [8],the number of chemicals commercially produced has increased exponentially in parallel with increasingindustrialization. Commercial chemical production has risen from 1 million tons in 1930 to 400 milliontons in 2001 [9], and over the past few decades the global sale of chemicals has increased by a factor of25 from U.S. $171 billion in 1970 to US$4.1 trillion in 2012 [10]. As of 2012, the number of industrialchemicals on the global market was estimated to be around 143,835 [10].

A number of large population biomonitoring studies have revealed widespread chemicalexposures from the “womb to the tomb” with levels in humans and wildlife that are known tocause adverse health effects. Such studies include the National Health and Nutrition ExaminationSurvey in the USA [11], DEMOCOPHES survey in Europe [12], German Environmental Surveysin Germany [13], Flemish Environment and Health Study in Belgium [14], Esteban cross sectionalsurvey in France [15], Russian Federation [16] and the BIOAMBIENT ES in Spain [17] in additionto national birth cohort studies conducted in Denmark (Danish National Birth Cohort) [18], France(French Longitudinal Study of Children Survey) [19], Norway (Norwegian Mother and Child CohortStudy [20], and Spain (The Spanish Environment and Childhood Research Network) [21]. Thereare also ongoing epidemiological studies such as the Cross-Mediterranean Environment and HealthNetwork project, which aim to demonstrate an integrated methodology for the interpretation of humanbiomonitoring data that will allow researchers to quantitatively assess the impact of chemical exposureson human health [16]. Despite these efforts, human toxicity data is lacking for most chemicals inwidespread use, even when population-wide exposures are documented [22].

Disturbingly, many environmental chemicals are found in human breast milk and the placentawhere they directly affect the foetus [23]. A landmark study conducted by the Environmental WorkingGroup identified 287 chemicals in cord blood, raising the profile of the widespread exposures toeveryday chemicals [24]. More recently, the Canadian “pre-polluted study” identified 137 chemicalsin cord blood, 132 of which are reported to cause cancer and 133 that cause developmental andreproductive problems in mammals [25]. The brain of a foetus and infant is particularly vulnerable asthe central nervous system is the dominant repository of foetal fat and many environmental toxicantsare lipophilic. Consequently the health impact of chemical exposures is most evident in paediatricmedicine where chronic disease has overtaken infectious diseases as the major burden of paediatricillness [26]. The obvious and extensive impact of environmental chemicals on children’s health, hascontributed to paediatrics being the first medical discipline to identify chemical exposures as animportant health issue, with the American Academy of Paediatrics establishing an environmentalhealth committee in 1958 and publishing its first edition of Paediatric Environmental Health for cliniciansin 1999 [27].

While chemical exposure is ubiquitous in the general population, the Environmental JusticeHypothesis suggests that exposures are unevenly distributed. This hypothesis, which emerged

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in the 1980s following the publication of several studies in the USA [28–32] suggests thatenvironmental hazards are inequitably distributed according to class and race [33]. Yet, the strictbifurcation of communities into categories of Environmental Justice and Non-Environmental Justice isproblematic [34], because much of the literature is based on comparisons of exposure and risk betweendifferent populations, rather than on the toxicological and biological impacts of those exposures [35].Furthermore, while some minority groups and those with lower socioeconomic (SES) status arelikely to bear a greater burden of environmental toxicants given their lifestyle, proximity to wastesites, industrial emissions and poorer quality ambient air, biomonitoring studies have identifiedtoxicants in all individuals, the type and amount of which varies depending upon lifestyle factors andgeographical variation. For example higher SES individuals have been found to have higher burdensof mercury, arsenic, caesium, thallium, perfluorinated compounds, certain types of phthalates andbenzophenone-3 as a result of their lifestyle (fish consumption, dental history, homegrown vegies,cosmetic and sunscreen use) [36]. In contrast, lower SES individuals have been found to have higherlevels of lead, cadmium, antimony, bisphenol-A and other types of phthalates, which may be partiallymediated by smoking, occupation and diet [36].

3. Environmental Chemicals and the Origins of Chronic and Complex Disease

The dramatic rise in the number of commercially produced chemicals has resulted in exposure toindustrial chemicals being ubiquitous in both developed and developing nations and an increasingdisease burden that is not yet fully understood. The World Health Organisation estimates that4.9 million deaths and 86 million Disability Adjusted Life Years were attributed to environmentalchemicals in 2011 [10] and that approximately one-quarter of the global disease burden, and morethan one-third of the burden among children under the age of 5 is due to modifiable environmentalfactors [37]. A recent review further estimated that the disease burden in the European Union associatedwith exposure to endocrine disrupting chemicals alone, cost $209 billion or 1.23% of Europe’s GDP [38].

Many of the chronic diseases that have substantially increased in prevalence over the past 40 years,appear to be related in part to developmental factors associated with nutritional imbalance andexposures to environmental chemicals [39]. For example the “developmental obesogen” hypothesisis used to explain why the prevalence of obesity among school age children between the early 1970sand late 1990s has doubled or trebled [40]. Whilst obesity prevalence has begun to plateau, a growingnumber of chemical obesogens such as organochlorine pesticides [41–43], bisphenol A [44], PCBs andphthalates [45] have been found in-utero and are implicated in the development of obesity later inlife [46,47].

The concept of early life origins of disease was first brought to light in 1934 by Kermack andcolleagues who suggested that decreased death rates due to all causes were the result of improvedchildhood living conditions [48]. This was later expanded upon by Neel in 1962 [49], Forsdahl inthe 1970s [50,51], and in the late 1980s by David Barker who associated nutritional deficits duringfetal development and consequent low birth weight, to increased risks for obesity, diabetes andcardiovascular disease and thereby came to be considered as the father of the “Fetal Origins of AdultDisease” hypothesis [52]. Whilst the Developmental Origins of Health and Disease (DOHaD) hashistorically focused on nutrition, understanding of the role of early life experience in chronic diseaseaetiology requires an integrated analysis of all aspects of the environment (nutrition, psychosocialstress, drugs, microbiome and environmental pollutants) and how they interact to cause disease [53].Thus, the DOHaD has far reaching implications in clinical practice, and implies a need for clinicians toundertake an extensive paediatric, environmental and occupational exposure history and consider therole of nutrition and environmental chemical exposures during critical windows of development tounderstand the development of chronic illness in later life.

The list of diseases that may be caused or exacerbated by environmental chemical exposures isextensive and growing. These diseases include diabetes [54,55], infertility [56–58], testicular dysgenesissyndrome [59,60] which encompasses hypospadias [61,62], cryptorchidism [63,64], testicular

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cancer [65], and poor semen quality [66–68], ovarian dysgenesis syndrome [69], neurodegenerativediseases such as Alzheimer’s Disease [70], respiratory disorders such as asthma [71] and chronicobstructive airway disease [72], as well as autoimmune diseases [8], obesity [73–75] and cardiovasculardisease [76–78]. Emerging evidence is also linking industrial chemicals to a pandemic ofneurodevelopmental disorders [79] the implications of which have devastating consequences onfamily’s and the global economy [80,81]. Whilst the cause of these neurodevelopmental problems is notyet clear, genetic factors are acknowledged as only playing a minor role [82,83] and several hypothesespoint to environmental influences involving aberrations in the gastrointestinal microbiota [83],industrial chemicals [81,84,85], malnutrition [86,87], viruses and drugs [88] as potential causal agents.

Environmental factors are also believed to account for a significant portion of cancer mortalityworldwide [89]. There is a growing body of evidence associating various toxicants withcancer including: air pollutants like asbestos, radon, hexavalent chromium, tobacco smoke andbenzo(a)pyrene with lung cancer [90–93]; endocrine disrupting chemicals such as pesticides, dioxins,furans and PCBs with an increased risk for breast cancer [94], endometrial, testicular and prostatecancer [95–98]; arsenic and disinfection by-products with bladder cancer [99,100]; vinyl chloride withliver cancer [101], benzene with leukemia [102]; and pesticides with childhood leukaemia [103–105].Even though the incidence of cancer attributable to environmental chemical exposures has not beendefinitively established [106,107], the World Health Organization and the International Agency forResearch on Cancer (IARC) suggest that between 7% and 19% of all cancers are attributable to toxicenvironmental exposures [108,109]. According to cancer biologists, this estimate is likely to be agross underestimation, as many supposedly non-carcinogenic chemicals that are ubiquitous in theenvironment have been shown to exert low-dose effects that may contribute to carcinogenesis [110,111].This is of particular concern in light of the fact that cancer has now become the world’s leading causeof mortality [112].

Clinicians are also seeing a rise in the prevalence of patients with a shopping list ofongoing seemingly unrelated persistent complaints, which some have described as a “pandemicof idiopathic multimorbidity” [113]. While multimorbidity is associated with chemical sensitivity,it presents an increasingly common and confusing primary care dilemma often labelled asChronic Fatigue Syndrome [114,115], Systemic Exertion Intolerance Disease [114], Sensitivity-RelatedIllness [116], Idiopathic Environmental Intolerances [117], Fibromyalgia [118], ElectromagneticHypersensitivity [119], Sick Building Syndrome [120] and Multiple Chemical Sensitivity [114]. Theseconditions are diagnoses based on exclusion rather than any specific aetiology as they have noclear aetiology, pathogenesis, or recognised genetic or metabolic markers that can be observed withstandard laboratory testing. Despite the fact that the degree of hypersensitivity often parallelsthe intensity of the total body burden of bio-accumulated toxicants [121], patients with theseconditions are relatively understudied [122] and are frequently considered to have psychogenic illness.Such patients have complex needs, and frequently present with a multitude of health complaintsin different organ systems that often require attention from a range of medical specialists [123].It has been suggested that a common aetiological pathway for a diverse range of idiopathicenvironmental intolerances may involve environmental chemicals inducing oxidative stress andsubsequent mitochondrial dysfunction [124,125], in addition to low-grade systemic inflammationin multiple organ systems [124,126], and polymorphisms in nitric oxide synthase [125], antioxidantand/or detoxification genes [116,124], that result in a “toxicant-induced loss of tolerance” [127,128].It is further suggested that exposures occurring during critical windows of development play animportant role and that early life exposures are significant contributors to chronic diseases throughoutthe lifespan and across generations [96,129].

4. Chemical Risk and Chemical Risk Assessment

In contrast to the great majority of acute conditions and infectious diseases where cause and effectcan easily be established, exposure to low levels of thousands of environmental chemicals over a life

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span requires a paradigm shift in the way in which causality is established. Chemical risk is basedon the type and dose of chemical, combination effects, the timing of exposure, and individual riskfactors, yet the existing chemical risk assessment framework only involves hazard identification andexposure assessment [130], where hazard identification assesses the ability of a chemical to cause harmat various dosage levels, and exposure assessment evaluates the dose that might be received at targettissue after contact. Such assessments rely heavily on data extrapolated from human epidemiology,animal testing and cell culture/in vitro laboratory studies [131] that fail to account for multiple routesof exposure, mixture effects, transgenerational epigenetic effects or individual human risk factors suchas age, gender, genetics, nutrition, psychosocial determinants and comorbidities [130,132–134].

4.1. Dose Response and Low Dose Effects

Dose-response relationships follow the path laid by epidemiologist, Sir Austin Bradford Hill, andform the basis of most contemporary systems for chemical risk assessment and causation analysis [135].Such assessments involve giving increasing levels of an individual chemical to a group of test animalswith the key objective of providing a dose-response assessment that estimates a point of departure(traditionally the no-observed-adverse-effect (NOAEL) level or the lowest-observed-adverse-effectlevel), which is then used to extrapolate the quantity of substance above which adverse effects can beexpected in humans [110]. Endocrine disrupting chemicals pose a particular dilemma for chemicalrisk assessment as these chemicals can exhibit non-monotonic dose-responses whereby the effect oflow doses cannot be predicted by the effects observed at high doses [110,136]. In addition to thecomplexities involved with endocrine disruption, carcinogenesis is a highly complex process and agrowing number of scientists are questioning the use of linear dose-response models for classifyingcarcinogens, as these models do not account for the complex and permutable pathogenesis of manycancers [137].

4.2. Chemical Mixtures and “Something from Nothing” Effects

The prediction of health risks based on NOAEL not only fails to account for non-monotonicdose-responses, it also fails to reflect real-life exposures which typically involves exposure to multiplechemicals [138]. This may explain why pesticide formulations such as “Roundup” have been shown tobe significantly more toxic than their active principle (glyphosate), due to the inclusion of adjuvantsthat increase their potency yet are not accounted for in safety assessments [139]. Furthermore, theNOAEL approach does not consider “something from nothing” mixture toxicity whereby unpredictableadditive, antagonistic or synergistic adverse effects may occur at doses around, or below points ofdeparture [140]. For example, carpenters exposed to formaldehyde, terpenes and dust particles belowtheir point of departure are reported to exhibit dyspnea, nose and throat irritation, chest tightnessand productive cough [141] and complaints of headache, skin, eye, nose and throat irritation arereported in painters despite airborne exposure levels being below the known irritation levels forthe single chemicals [142]. Similarly, weakly oestrogenic chemicals that are too small to be detectedindividually can jointly increase the actions of potent, endogenous sex steroids [143] and chemicalmixtures can act synergistically to exert pro-carcinogenic and anti-carcinogenic effects that contributeto the accumulation of somatic mutations and instigate the hallmarks of cancer [110,144,145]. Inorganicarsenic is one such example. At high levels in drinking water, arsenic is a well-established humancarcinogen associated with bladder, lung and skin cancer [146], however at lower doses, its cancer riskmay depend upon other variables such as smoking, and on differences in individual susceptibility,either genetically based or via nutritional status or other conditions [147]. This observation parallelsthe well-established finding that smokers exposed to asbestos have a significant increase in lung cancerrisk compared to non-smokers [148].

One theory of how chemical mixtures may elicit unexplained effects, is based on the observationthat mixture effects commonly occur when chemical mixtures contain at least one lipophilic and onehydrophilic chemical [132]. Lipophilic chemicals promote the permeation of hydrophilic chemicals

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through mucous membranes [132]. This is important because lipophilic barriers in the body (skin andmucous membranes) serve as the body’s primary protection against the absorption of environmentalchemicals [149]. The octanol-water partition coefficient, or Kow, which classifies the lipophilic characterof a given chemical, is a useful parameter for environmental risk assessment that is used extensively byauthorities in the European Union [150]. Most lipophilic toxicants can permeate the body’s membranes,and lipophilic chemicals with a Kow greater than 2, are frequently used by the cosmetic industry aschemical penetration enhancers, as adjuvants in pesticides to increase the solubility of the activeprinciple and by the pharmaceutical industry in drug-delivery systems to enhance transdermal drugdelivery [151].

The evaluation of mixture effects is hampered by a lack of knowledge of the molecular pathwaysinvolved along with the large numbers of pollutants and their many potential combinations [152].Lifetime effects of exposure to chemical combinations are also largely unstudied [111], and mayonly become evident after people have become sick [132]. Thus, until a risk assessment paradigmis designed for mixture effects, traditional risk assessment tools need to be used with caution whenevaluating chemical mixtures [153].

4.3. Timing and Transgenerational Epigenetic Effects

Compelling epidemiological, pharmacological and toxicological evidence shows that thereare several vulnerable periods of growth and development. During these periods, environmentalinteractions with the immune system and genome can increase susceptibility to central nervous systemand metabolic diseases later in life [154]. Despite the fact that transgenerational effects arising from poornutrition and chemical exposures in utero are widely reported in the scientific literature [155–158], theimpact of epigenetic factors early in life remains largely unexplored in chemical risk assessment [159].This is made more poignant by emerging evidence that in utero and early-life exposures may leadto disordered immune responses in adulthood and lead to heritable, epigenetic modifications in theimmune responses of subsequent generations [137].

The first association of transgenerational inheritance of disease was documented in the Dutchfamine of 1944 to 1945 where nutritional deprivation in utero was associated with increased risks forobesity later in life [160]. Epigenetic inheritance involving environmental chemicals is documentedin the daughters of mothers who took the drug diethylstilbestrol (DES) to prevent miscarriages andlater went on to have a significantly higher risk of vaginal cancer and other health complaints [161].Similarly, emerging evidence of transgenerational effects in animal models links autism spectrumdisorders to an array of environmental factors such as stress or environmental enrichment, endocrinedisruptors such as vinclozolin and BPA, and inadequate nutrition [162].

Whilst the mechanisms by which the effects of exposure are transmitted through the germlineto the next generation are still unclear, the most plausible explanation for these associations is theoccurrence of epigenetic modifications involving DNA methylation, retained histone modification,tRNA fragments, and non-coding RNAs in somatic and germ cells arising from exposure to variousenvironmental agents during critical windows of development [163]. Genome-wide association studies,in contrast to single nucleotide polymorphisms (SNPs) are likely to provide an important tool to identifythe “susceptible biomarkers” to environmental chemicals [100]. The study of gene-environmentinteractions however, poses special challenges for clinicians because it requires the integration ofcomplex information derived from a comprehensive exposure history, assessment of nutritional statusand detoxifications pathways, and genetic profile.

4.4. Individual Factors

There are many individual factors that determine chemical exposure and risk of adverse healthoutcomes. They include; age, gender, ethnicity, genetics, nutritional status, intestinal microbiota andother lifestyle factors such as diet, smoking, exercise and hobbies, psychosocial determinants andcomorbidities [130,132–134], the co- or pre-administration of other drugs, [132,164] and epigenetic

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states [165]. Exposure to toxicants also varies widely amongst individuals depending upon: past andcurrent environmental exposures; occupation and health and safety practices; place of residence, workand/or school (proximity to vehicle exhaust, industry, mining, waste sites, industrial accidents, golfcourses, parks, farms, flight paths, etc.) which is likely to be influenced in part by socioeconomicfactors [36]; use of household products, chemicals and pesticides and appropriate use of safetyequipment; and access to clean air, water, food and soil.

4.5. New Horizons in Chemical Risk Assessment

Advances in the “omics” fields such as genomics, proteomics and metabolomics, enable thescreening of effects of chemical mixtures at the molecular level and the development of more sensitiveand specific methodologies for biological monitoring of combined exposures [138,166]. High-resolutionmetabolomics (HRM) that uses ultra-high resolution mass spectrometry with minimal samplepreparation can support high-throughput relative quantification of thousands of environmental, dietaryand microbial chemicals and measure metabolites in most endogenous metabolic pathways, therebyproviding simultaneous measurement of environmental exposures and their biologic responses [167].Renewed interest in the placenta as a potential biomarker of exposure and its contributions to long-termhuman health and disease was recently initiated by the National Institutes of Health: Human PlacentalProject following evidence of its impact on the health of the mother [168,169] and fetus [170–173].Prospective follow-up birth cohorts to examine the effects of early life programming will also beimportant [163]. Emerging technologies are also providing a mechanism to assess the allostatic loadat the clinical level. For example, biomolecular adducts formed when a xenobiotic or its metabolitebinds to biological molecules (DNA or proteins), are a useful tool to assess exposures to non-persistentchemicals in blood such as organophosphates and aromatic amines before clinical consequencesappear [174].

Chemical risk assessment can be vastly improved by gaining better information about the totalityof exposures across the life span (exposome) [175]. Prospective, population-based cohort studies haverecently started to implement these methods using the exposome framework [166]. Consequentlyenvironmental health scientists are exploring new ways to strengthen the integrity of chemicalrisk assessment using the principles of systematic review [176,177] and some new initiatives arecontributing to the refinement and codification of methodological approaches for systematic review andmeta-analysis tailored to the specificities of environmental health [178]. To date there have been severalattempts at establishing systematic reviews for evaluating data on chemical toxicity [179] includingThe Navigation Guide [176], the Evidence-Based Toxicology Collaboration [180], the PROMETHEUSproject by the European Food Safety Authority [181], Integrated Risk Information System (IRIS) andTox21 by the joint US EPA, Food and Drug Administration and National Institute of EnvironmentalHealth Sciences [182,183], ToxRTool by the European Commission [184], REACH by the EuropeanChemicals Agency and KIimisch Ring Test [185].

Further developments to improve toxicity testing based on animals include a new design fromthe National Research Council for cellular-response networks that take into consideration advances intoxicogenomics, bioinformatics, systems biology, epigenetics, and computational toxicology therebyallowing scientists to uncover how environmental chemicals may lead to toxicity [134]. Emerging toolslike the maximum cumulative ratio will further help to identify a person’s cumulative exposure tomultiple chemicals over a lifetime [186].

5. The Challenges and Failure of Chemical Regulation

Once an industrial chemical has been tested and its point of departure has been established,it is up to government organisations such as the Environmental Protection Agency, US NationalInstitute for Occupational Safety and Health, Safe Work Australia, European Commission’s ScientificCommittee on Occupational Exposure Limit Values and non-governmental organisations like theAmerican Conference of Governmental Industrial Hygienists (whose guidelines have been widely

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adopted in English speaking countries) to develop ambient air and occupational exposure limits.This process is frequently conducted in consultation with industry, involving scientists employed byvarious corporations, taking into account what is easily achievable in the workplace [187,188], alongwith a consideration of economic output and future innovations.

Legislation and the threat of litigation is a powerful motivating force that encourages employersand manufacturers of industrial chemicals to comply with their occupational health and safetyrequirements. Yet, exposure standards frequently differ from country to country depending upon theapproach adopted. In the USA, the “low dose linear extrapolation” approach is favoured and legislatedthrough the Toxic Substance Control Act (TSCA), as opposed to the “margin of exposure” approachused in Europe and regulated through REACH (Registration Evaluation, Authorisation and Restrictionof Chemicals) [189]. The stark difference between the two is that REACH is a preventative approachthat places the burden of proof on industry to show safety, as opposed to TSCA where the burden ofproof is on the government to show harm [130]. As both of these systems primarily focus on industrialchemicals, numerous regulatory authorities have been established to regulate chemicals in food,cosmetics, pesticides and medicinal products. The chemical industry has exploited the inadequacies ofweak laws and regulations, inefficient enforcement, regulatory complexity and fragmented overlappingauthorities, to enable the introduction of untested chemicals into the commercial products and theenvironment [111,190]. Furthermore, non-occupational exposure standards for indoor air quality inresidential environments are lacking, despite organisations such as the World Health Organisation [191]and the US Environmental Protection Agency [192] producing numerous reports and guidelines onindoor air quality.

The wide variation in exposure standards across jurisdictions along with vast numbersof commercial chemicals in widespread use that have not been adequately assessed forneurodevelopmental toxicity, endocrine disruption or other toxic effects, points to inadequacies incurrent chemical risk assessment procedures. Such inadequacies were highlighted as early as the 1970sby Bruce Ames who subsequently developed the Ames test for assessing the mutagenic potential ofchemical compounds [193]. More recently, existing chemical risk assessment practices have come underscrutiny from various governmental and non-governmental bodies including the US EnvironmentalProtection Agency [194], National Resource Defence Council [190], European Union (who respondedby developing REACH), the National Academy of Sciences and the Institute of Medicine [130] andmedical organisations such as the American Medical Association [195] and the American Academy ofPaediatrics [196].

The availability of scientific information is fundamental to the ability to understand and managerisk and form the basis for regulatory action. However, while compelling epidemiological, animaland in vitro evidence is required to prove harm from a chemical exposure [111], there is a lackof well-accepted tools to objectively, efficiently and systematically assess the quality of publishedtoxicological studies [197] making it difficult to assess health risks associated with low level exposureto hundreds of chemicals over a life time. Thus, for almost every conclusion about chemical-relatedhealth risks, it is possible to find a dissenting view [179] and the vast majority of scientific reviewsconclude that “more research is needed”.

6. What Are the Barriers for Chemical Assessment in Clinical Practice?

While chemical risk assessment requires the application of multiple scientific fields to public healthand regulatory issues, it is up to individual clinicians to determine the relevance of the many issuesinvolved to the current and future health needs of their individual patients. Environmental chemicalassessment in clinical practice therefore requires the personalization of medicine using the translationof a complex knowledge base to determine an individual’s body burden of toxicants, along with theirpersonal risk factors and health status. Yet, despite the many scientific developments occurring in thearea of chemical risk assessment, the discrepancies amongst leading authorities in their interpretationfor evidence of harm makes it difficult for clinicians to translate scientific information into clinical

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practice. Furthermore, while clinicians must deal with the consequences of environmental chemicalexposures and remain one of the most often accessed and most trusted sources of information aboutthe health and the environment [198], there is widespread agreement that clinicians lack adequateinformation and training with respect to environmental risks and health [199,200].

6.1. What is Environmental Medicine?

A lack of clinical training in environmental medicine may be partly due to inconsistencies indefining “environmental medicine” and the confusion as to where it fits in relation to other specialtiessuch as public health and occupational medicine. In the mainstream scientific literature, environmentalmedicine is defined as the evaluation, management, and study of detectable human disease or adversehealth outcomes from exposure to external physical, chemical, and biologic factors in the generalenvironment [199,201]. This is in contrast to occupational clinicians whose definition of environmentalmedicine varies depending upon the country and include: “exposures arising from industrial activitiesat a workplace” (Australia), “embracing any influences on health and disease that are not genetic” (UK),or as “a branch of medical science which addresses the impact of chemical or physical stressors on theindividual or group in a community” (USA) [202]. To add to the confusion, public health cliniciansdefine environmental medicine more broadly as “issues in the physical environment which impact onhealth, encompassing quality of air, water and food” [202]. Consequently environmental medicinehas become a specialty field under the guise of “occupational and/or environmental medicine” and“public health” with the majority of “environmental physicians” focusing on public health issuesrather than patient-centered clinical practice [203]. Wide inconsistencies in the definition for the term“environment”, has further ramifications for establishing environmentally attributable risk estimates.For example researchers and publications that define the environment in the narrow sense (air, water,food, and soil pollutants) tend to have smaller attributable risk estimates, whereas researchers andpublications that refer to the environment in the broadest sense (including lifestyle factors, occupationalexposures, and pollutants) have consistently larger risk estimates [106].

Relegating environmental health to a specialty field is highly problematic when environmentalchemical exposures are implicated in many of the conditions seen by clinicians on a daily basis, yetthe tools and expertise to adequately assess or manage these exposures are not widely available [200].Furthermore, few doctors take adequate occupational or exposure histories [204] or refer patientsto environmental physicians [123] and therefore environmental exposures are seldom identifiedin disease causation [111]. Consequently the cadre of environmental oncologists, researchers andclinicians trained in environmental health are relatively small, which may explain why environmentalhealth is largely excluded from national policy [111].

6.2. Medical Training

There is a widely acknowledged need for greater awareness about chemical assessment amongstclinicians. The need for general clinicians to familiarise themselves with the health impacts ofenvironmental chemical exposures was highlighted in 1967 at a conference by the American MedicalAssociation’s National Congress on Environmental Health Management, and was further highlightedby the American College of Clinicians [205,206] as well as being a focus of the International Federationof Environmental Health in 1991 [207] and 2013 [208]. Despite the recognized need for clinicaleducation on environmental chemicals, there appears to be a severe lack of environmental healtheducation in medical undergraduate curricula. The Institute of Medicine has been particularlyvocal about the lack of environmental health training as evidenced by the publication of the book“Role of the Primary Care Physician in Occupational and Environmental Medicine” [200], and thereport “Environmental Medicine—Integrating a Missing Element into Medical Education” [199],which outlined a six competency-based learning objectives for medical students. This is furtherreinforced by the World Health Organisation’s report “Environmental Health and the Role of Medical

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Professionals” [209], which highlights the medical professionals role in assessing, investigating,diagnosing, monitoring, treating and preventing environmentally-related disorders.

The lack of environmental education for clinicians can be seen to be due to competitionfrom other disciplines in crowded medical curricula, lack of funding and a lack of appropriatelytrained academics [210]. A significant proportion of undergraduate medical training is devotedto pharmacology as opposed to toxicology [211] or environmental health, with the exception ofmedical toxicology, a specialty field involving acute high dose exposures confined to emergencyclinicians [212]. Furthermore, nutrition is rarely taught in undergraduate medical training despite thefact that the nutritional state of the person affects the impact and metabolism of toxicants in key Phase 1and 2 metabolic detoxification pathways [132]. Not surprisingly, a recent survey of medical schoolgraduates found that more than one-third of respondents said they received “inadequate” instructionin environmental health [213].

Both the World Health Organisation [214] and the American Academy of Paediatrics [27]acknowledge the lack of training in medical schools, and recommend that children’s environmentalhealth be incorporated into the training for health care providers. Others have noted that obstetriciansand gynaecologists are well positioned to prevent hazardous exposures in light of the irreversibleimpacts on health arising from chemical exposures in utero [215]. Aside from nutrition, smoking anddrinking during pregnancy, obstetrics-gynecology education has been largely void of environmentalhealth [216]. A recent report by the International Federation of Gynecology and Obstetricsrecommended that reproductive and other health professionals advocate for policies to preventexposure to toxic environmental chemicals, work to ensure a healthy food system for all, makeenvironmental health part of health care, and champion environmental justice [85]. Calls to action arestarting to be heard with the Association of American Medical Colleges recent webinar on “TeachingPopulation Health: Innovative Medical School Curricula on Environmental Health” [217] outliningthe need to educate undergraduate medical students in environmental health which included links tothe American College of Medical Toxicology’s Environmental Medicine Modules [218].

6.3. Environmental Health Data and Its Relevance to Clinical Practice

The sheer number of scientific journals, non-governmental organisations, associations,professional societies, environmental medicine practitioner organisations and governmental agenciesdedicated to environmental health is enough to leave clinicians overwhelmed and despondent inever gaining a grasp of this complex and ever growing field. The number of journals dedicatedto public, environmental and occupational health under the category “Clinical Medicine” in theWeb of Science database grew from 101 in 2005 to 142 in 2010 yet very little of the vast amount ofliterature on environmental health is actually published in general medical journals. This is likelyto be due to a variety of factors. Firstly, evidence about environmental exposures based on animalstudies in the absence of human experimental data is considered “weak evidence” by the medicalfraternity and outside the comfort zone and time constraints of most clinicians [219]. In addition, whilstepidemiological studies are important tools for determining risk, they can be limited by often failingto take into account the role of individual differences reflected in subpopulations [220]. For much ofthe history of clinical trials, the treatments under investigation were assumed to apply to anyone withthe relevant clinically defined condition [221]. However the emerging “omics” fields and molecularcancer epidemiology, has led to the recognition that clinical trials need to be redesigned to account forindividual variations (N = 1) arising from one’s genomic profile, lifestyle and environmental exposures.

How do we accommodate evidence in the context of individual patients? As it is not viableto devote resources to generate randomised clinical data on patients whose variants are so uniquethat they represent a small minority of the community, a shift is needed in the way we think aboutevidence-based medicine. Despite rapid advances in technology and the volume of literature publishedabout the adverse health effects arising from exposure to environmental chemicals, health care systems

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have fallen far short in their ability to translate knowledge into practice and to apply new technologysafely and appropriately [222].

7. How Can Clinicians Assess Environmental Chemical Exposures?

Whilst biomonitoring is an established approach to evaluate the internal body burden ofenvironmental exposures, the use of biomonitoring for exposome research is limited by the highcosts associated with quantification of individual chemicals [167]. Interpretation of the presence ofchemicals in human tissues has also been the subject of much controversy, as its presence cannot betaken to imply that there will be adverse functional consequences [123,223]. For example blood andurine samples generally only reflect recent exposures to toxicants (heavy metals, persistent organicchemicals, organophosphate (OPs) and carbamate pesticides); hair and nails reflect past exposures(pesticides, heavy metals, polychlorinated biphenyls and polyaromatic hydrocarbons), are easilycontaminated and difficult to collect in a standardized way; and many other biological matricessuch as human milk, saliva, adipose tissue and meconium lack reliable reference values for humanpopulations [138].

Resources and tools to educate clinicians and elicit personal environmental health data in theclinical setting are limited in scope and applicability. For example, the Australian NHMRC 2011Standard for Clinical Practice Guidelines portal does not provide any guidelines on how to assessenvironmental chemical exposures, despite the fact there are extensive guidelines for conditionslike diabetes, which are known to be influenced by chemical exposures. The lack of guidelines iscompounded by a lack of conventional pathology tests to assess environmental chemical exposures.In addition, the knowledge required to understand what, how and when to assess environmentalchemical exposures requires extensive knowledge on individual toxicants, their metabolites and/orthe product of toxicant interactions with endogenous targets [174], which is not generally consideredwithin the realm of most clinicians.

Tools that are available such as the EPA’s Office of Pesticide Protection questionnaire, theCDC’s Agency for Toxic Substance and Disease Registry “Taking an Exposure History Guide”,The Navigation Guide, Eco-Health Footprint Guide (Global Health and Safety Initiative), QuickEnvironmental Exposure and Sensitivity Inventory (QEESI), WHO Paediatric Environmental Historyto name but a few, are unlikely to be known by most general clinicians, and have either not beenvalidated and/or require lengthy periods of time to complete, which may not always be practicalin a clinical setting. Consequently clinicians and those specialising in idiopathic multimorbidity, arelikely to have developed their own assessment procedures to assess their patient’s susceptibility orexposure to environmental toxicants. Such procedures may include extensive historical inquiries(paediatric, occupational and environmental exposure histories) along with an assessment of theirpatients’ metabolic, nutritional, genetic, and exposure profiles and include unconventional testsperformed at pathology laboratories from around the globe such as Acumen Labs, Nutripath, DoctorsData, Genova Diagnostics, Healthscope Functional Pathology, Mycometrics, US Biotek Laboratories,Great Plains Laboratory and AsureQuality Labs, amongst others. Such assessments may come atconsiderable expense to their patients and as exposure standards are not available for many biomarkers,these clinicians must interpret the data without the benefit of published normal ranges or specificdiagnostic criteria.

To assess environmental chemical exposures in patients, the challenge for clinicians is to askrelevant questions to elicit toxicant sources and exposure, identify the most relevant tests and todigest data from multiple streams (traditional medical data, “omics” data and quantified self-data),and place this information in the context of individual patients in a way that has measurable andmeaningful outcomes. Only by doing so, can medicine shift the focus from treating disease, toprevention and wellness.

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7.1. Lessons in History—Asking the Right Questions

The history of medical care is littered with examples of missed opportunities, wasted resources andcounter-productive policies, due to the inability to effectively assemble and act on available evidence ontoxicant exposure [179]. Environmental tobacco smoke, asbestos, lead dust, benzene, polychlorinatedbiphenyls, chlorofluorocarbons, lead and organochlorine pesticides are just some examples wherewarnings were ignored decades prior to the emergence of devastating public health issues [224].History also provides examples of doctors whose observations at the clinical level, in addition to thepower of rapid action, resulted in significant improvements in public health. For example, in the 18thcentury, British surgeon, Sir Percivall Pott, without knowing the cause or mechanism of action, stoppedan epidemic of scrotal cancer in chimney sweeps by asking them to improve their genital hygiene [225].Furthermore, in 1854, Dr. John Snow who is credited as the first epidemiologist, was able to prevent anoutbreak of cholera by dismantling a water pump handle in Broad St, London, despite great criticismfrom his peers [226].

7.2. The “Omics” Revolution and Personalised Medicine: A Match Made in Heaven

Following completion of the Human Genome Project in 2003 in conjunction with the rapidadvances in bioinformatics, the “omics” fields exploded onto the scene, challenging our understandingof the nature and cause of disease, whilst also shifting the focus to what it means to be well. Clinicalgenetic testing has transformed from being centred on mutation detection for Mendelian disorderslike sickle cell disease to personal genomic data as a way to predict ancestry and assess diseaserisk. The emergence of hand-held devices such as the “SNIP doctor” for analysing single nucleotidepolymorphisms, has bridged the gap from the bench to the bedside [227]. Whilst the brunt of thesediscoveries has yet to infiltrate clinical practice (because it takes an average of 17 years to incorporatescientific discovery into clinical practice [222]), the ramifications of these findings will provide moreprecise treatment for individuals and issue a new era in personalised medicine.

Breast cancer risk provides a good example. Whilst the aetiology of breast cancer is still not fullyunderstood, there are several known risk factors including: the age of menarche/parity/menopause;family history of breast cancer; length of time of breast feeding; body mass index; drugs (hormonereplacement therapy, oral contraceptive pill); exercise; alcohol intake; and cigarette smoking [228,229].Given that the prevalence of gene mutations (BRCA1, BRCA2) for women diagnosed with breast cancerare low (5.3% and 3.6% respectively) [230], it has been suggested that low-penetrance susceptibilitygenes combined with environmental factors may be important risk factors [231]. Advances ingenomics have identified several gene variants (single nucleotide polymorphisms (SNPs)) in keydetoxification pathways that maybe associated with breast cancer susceptibility [232–236]. Howeverfew of these variants (COMT, CYP1B1, GSTP1, MnSOD, MTHFR) have been shown to contributeto breast cancer risk individually except when these polymorphisms are combined [237], or in thepresence of relevant environmental chemical and lifestyle exposures [238,239]. This is significant inlight of the fact that unique populations of various ethnicity have been shown to have polymorphicvariants in detoxification enzymes, which may predispose them to increased adverse health effectsfrom environmental chemical exposures [240,241]. For example, despite the low incidence of breastcancer amongst Asian women [242], a recent meta-analysis to determine the role of MTHFR C677Tpolymorphism in breast cancer risk, showed a strong significant association between TT genotypeand breast cancer which is far more prevalent in the Asian population compared with the Caucasianpopulation [235]. This may explain why US-born Asian women have an almost two fold higherincidence of invasive breast cancer than foreign-born Asian women [243], implying that epigeneticeffects involving lifestyle, dietary, and/or environmental factors are likely to play a role. The results ofthese findings, may explain why so many risk factors have been implicated in breast cancer and otherchronic diseases, and yet a causal relationship has not been definitively established.

As stated by Dr. Francis Collins, Director of the US National Institutes of Health “genetics loadsthe gun and the environment pulls the trigger”. Thus establishing an individual’s risk to environmental

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chemicals based on the presence of low penetrance genes (SNPs) alone is limited unless it is combinedwith the potential epigenetic effects of pathological, developmental, dietary and environmentalchemical exposure history across the lifespan [244]. The concept that the phenotype is the consequenceof gene-environment interaction was highlighted by Archibald Garrod in 1902 who suggested thatindividual differences in genetics could play a role in variation in response to drugs, and that thiseffect could be further modified by the diet [245]. However, while genetic testing is providinggreater understanding of disease risk, the application of gene testing at the clinical level is fraughtwith challenges.

Very few of the one million plus SNPs identified in genome wide association studies have clearfunctional implications and actionable outcomes that are relevant to mechanisms of disease [246],which is why clinicians perceive the analysis of genetic data as requiring considerably more time andwork with uncertain outcomes [247]. Secondly clinical guidelines for genomic testing is still in itsinfancy, such that there is a poor understanding of the effect of individual alleles, many of whichappear to be non-sense mutations but may at a later date prove to be of clinical relevance especiallyin the context of other alleles, epialleles and environmental exposures [248]. Furthermore, theaccuracy of laboratory analysis of genetic information and interpretation of results may vary amongstdirect-to-consumer genetic testing companies depending upon their quality control standards [249].Despite the remarkable advances in biomedical research and in particular, the field of genomics in thepast twenty years, concerns have been raised about the lack of knowledge and skills in genetic andgenomic testing, interpretation of test results, communication of results to patients and families, andbasic genetic counseling amongst general non-academic clinicians [250,251]. Finally and perhaps mostimportantly, clinical genomics requires an understanding of the ethical, legal and social considerationsassociated with genomic profiling including employment and health insurance nondiscrimination,patient’s rights, informed consent, disclosure, microarray screening for pregnancy, cost/benefit ratio,drawbacks versus perceived benefits, genetic counselling, protection of privacy and data protection [252–254].Clinicians will therefore need educational programs that target relevant scientific, clinical, ethical,legal, and social topics and support systems that address structural and systemic barriers to theintegration of genetic medicine into clinical practice [251].

7.3. Citizen Science and Mobile Technologies

It is clear that the impact of environmental chemical exposures is an issue that requires actionat many levels and must ultimately include the general community. Thus, civil society, includingnon-government organisations and civilian advocates can play a vital role in shedding light on thenature and extent of chemical exposures and their impacts. As such, citizen science or “participatoryurbanism” is an emerging field that shows great promise in the scope of environmental awarenessand regulation [255]. This became evident as early as the 1960s when a citizen science project revealedwidespread contamination from radioactive fallout from atomic weapon testing through the analysisof strontium 90 in baby teeth collected from around the world, leading to the signing of the PartialNuclear Test Ban Treaty in 1963 [256].

The potential for participatory citizen science has expanded enormously since the 1960s.Consumer’s appetite for health information is evident by the 40,000+ smartphone health applicationsnow available [257] and the fact that almost 60% of mobile phone users have downloaded a healthapp [258]. Furthermore, genomic profiling is now available for as little as $99 from companies like23andMe who have databases in excess of one million clients. With more tools at their disposal, webapplications have enabled citizens to take a proactive approach to make informed health-care decisions.No longer passive recipients of health care, these “e-patients” have given birth to the quantifiedself-movement, and irrevocably changed the traditional doctor-patient relationship making way forthe participatory medical model. Furthermore, the advent of the internet along with rapid advancesin mobile computing, wearable devices, nano-biosensors, lab on a chip technology, geographicalinformation systems, the quantified-self movement, the internet of things, big data analytics and cloud

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computing, represent disruptive innovations that promise to create a fundamental shift in biologicaldiscovery. Such advances, which enable the real-time measurement of physiological and psychologicalstates along with environmental measures, offer the ability to better predict, detect and prevent diseasebrought on by chemical exposures and thus radically accelerate our understanding of the health impactof environmental chemical exposures [259].

Widespread adoption of information technology applications requires behavioral adaptations onthe part of clinicians, organizations, and patients [222] and the ability of technology designers to buildbetter tools and platforms that allow patients to share data with their doctors in order to augmentexisting medical knowledge and practices [247]. Whilst citizen science has the potential to buildimportant bridges between scientists, clinicians and the public with positive outcomes for all [260],clinicians need to be receptive to the shift in the availability of knowledge to the public and be capableof answering questions that might arise so they can direct patients to credible and reliable resourceswhen appropriate [261]. Engaging volunteers in rigorous science, global-scale citizen science projectsalso provide an excellent opportunity to promote awareness, and educate and empower individualsand clinicians to find solutions to problems that would otherwise be large and overwhelming [260].

While citizen science and mobile technology has the potential to engage the wider communityin monitoring and reducing exposures to environmental pollutants, currently there is a lack ofintegration between data sources and a key challenge is the integration of big health data streams.Incorporating “big data” arising from traditional medical data, “omics” data and quantified self-datato routine clinical care will be a formidable and challenging task, and yet one that is vital for theemergence of personalised medicine that is predictive, personalised, preventative and participatory(4Ps). This challenge has been taken up by the field of systems biology, which uses computationalmathematical tools that promise to unify multiple data sets—personal, clinical, genomic, geographicaland environmental data. Systems biology therefore provides the foundation for personalised medicinewhere the patient becomes an integral part of the identification and modification of disease related riskfactors and the clinical decision-making processes takes advantage of the most up-to-date scientificknowledge [262].

7.4. Tomorrow’s Doctor

The failure of regulatory authorities to manage risk associated with environmental chemicals, inaddition to the widespread and growing number of chemicals found in the human population, providesclinicians with unique and important roles to play in identifying and preventing environmentalchemical exposures. While there some clinicians who are supported by integrative/functional medicineassociations that are rising to meet this challenge, there are no standard practice models and theseclinicians have had to engage in continual education, develop their own clinical assessment tools, andnavigate a path through the complex landscape of laboratory tests and the emerging science in multiplefields. This is an extremely challenging task, as conducting environmental chemical assessment at theclinical level includes (but is not limited to):

‚ Establishing the patient’s inherent susceptibility to environmental chemicals through assessmentof their demographics, ethnicity, socioeconomic status, comorbidities, nutritional andgenomic profile.

‚ A detailed place history that includes places of residence and work across the lifespan andthroughout the week including primary modes of transportation and an assessment of thepatients living conditions including their proximity to traffic and other sources of air pollution andpotential sources of lead and other heavy metals, mould, dust, indoor air pollution and chemicalsin building materials, furnishing and consumer products.

‚ An obstetric, paediatric, environmental and occupational exposure history that includes a detaileddietary history, drinking water sources, pharmaceutical and recreational drug use and generallifestyle factors including the use of chemicals in the home and garden, cooking utensils, cleaningmethods, personal care products and consumer goods.

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‚ A family history that includes previous generations.‚ A detailed symptom history that includes a timeline from the perinatal period and enquiry into

multiple organ systems.‚ A physical examination to look for physical signs of metabolic, neurological, reproductive or other

disease and co-morbidities.‚ Assessing current toxic load through performing various biomonitoring tests that include

assessment of biomarkers in various body tissues to assess long term accumulation of toxicants aswell as short term exposures.

‚ A consideration of external data sources such as geographical information systems andgovernmental or non-government environmental pollution reporting, ambient air monitoring,drinking water quality and any crowd-sourced data.

‚ Networking with other professionals who can assess the patient’s home and/or workplace toestablish sources of exposure.

‚ Keeping up with the latest regulations and scientific information on environmental chemicals andhow they may be assessed as well as their interactions with each other, different diseases andindividual patient factors.

To achieve this, clinicians need to possess a cluster of related knowledge, skills and attitudes inthe fields of genomics, nutrigenomics, microbiology, hygiene, toxicology, occupational health, publichealth, epidemiology and, from a clinical perspective, nearly all fields, as well as general medicine,paediatrics and oncology. In addition to clinicians dedicating themselves to this task, the politicsand economics of contemporary medicine need to support the dissemination and implementation ofthis kind of information. However there are many obstacles that hinder this process including thecomplexities involved in integrating data from numerous emerging fields, time constraints imposed onclinicians, educational requirements, the need for population and individual biomonitoring, the lack ofclinical assessment tools, pathology facilities and adequate risk based regulation, profit based fundingmodels that favor treatment over prevention, and the lack of political will to implement drastic changesin how we produce, monitor and regulate chemicals. Ultimately the issues raised by environmentalchemical exposures are far greater than those that can be faced by clinicians, as they affect all peopleand indeed all life on earth. There is a need therefore for concerted action at all levels including actionsby individual patients, clinicians, medical educators, regulators, government and non-governmentorganisations, corporations and the wider civil society in order to understand and minimise the extentof toxic exposures on current and future generations.

8. Conclusions

Large population biomonitoring studies have revealed widespread exposures to environmentalchemicals at levels in humans known to cause adverse health effects. Despite emerging evidenceassociating many of these chemicals with chronic diseases typically seen in general clinical practice,environmental chemical assessment has largely been overlooked in clinical practice. Part of thereason lies in the scientific complexities involved, inadequacies in chemical regulations and chemicalrisk assessment, inconsistencies in defining environmental medicine, a lack of information onenvironmental chemicals in general medical journals, inadequate pre- and post-graduate medicaleducation on environmental medicine, the limitations of current biomarkers and laboratory tests, alongwith time, funding and political constraints that limit the use of available tests in clinical practice.

Assessing environmental chemicals in clinical practice may very well be the toughest challengefacing medicine today. Determining susceptibility to environmental chemicals requires a sophisticatedunderstanding of each individual patient and the use of increasingly refined approaches thatincorporate extensive paediatric, environmental, geographical, occupational and lifestyle data. Theclinical assessment of environmental chemicals also involves embracing the gene-environmentparadigm and moving beyond reactive disease models to one that is proactive and preventative,

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whilst also acknowledging the vital role patients play in their own wellbeing. Recent developmentsin the fields of systems biology, and the “-omics” fields and advances in peer-to-peer wireless sensornetworks, may soon offer tools that provide a bridge between multiple disciplines and herald a newera in personalised medicine that unites clinicians, patients and civil society in the quest to understandand master the links between the environment and human health.

Acknowledgments: We have received no funds to publish in open access.

Author Contributions: Nicole Bijlsma and Marc M. Cohen contributed equally to the original idea for the paperand drafting, revising and approving the manuscript.

Conflicts of Interest: The authors declare no conflict of interest.

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